Primary cilia dysfunction has been linked to numerous human diseases and genetic disorders, which present with a wide range of clinical features. Primary cilia have been found on the macula densa cells, but its role in the regulation of kidney function is unclear. The macula densa mediates tubuloglomerular feedback (TGF) by detecting the increases in NaCl concentration and promoting the release of adenosine or ATP that constricts the afferent arteriole. However, little is known about the role of cilia in the macla densa in the regulation of renal hemodynamics, salt and water excretion. Our preliminary data indicate that elevations in tubular flow in the isolated perfused juxtaglomerular apparatus (JGA) preparations increase macula densa intracellular calcium concentration, activates nitric oxide synthase 1 (NOS1) and attenuates TGF response. However, the role of the cilia on the macula densa as the flow sensor initiating this response remains to be determined. Normally increases in sodium delivery to the macula densa induce TGF response and constrict the afferent arteriole. However, following volume expansion in response to salt loading, sodium reabsorption in the proximal tubule is inhibited resulting in sustained elevations in flow to the macula densa. Under these conditions we propose that the primary cilia are stimulated, raise intracellular calcium and enhance the formation of nitric oxide that inhibits and resets TGF response. The resetting of TGF is an essential modulatory mechanism to allow for the rapid excretion of a salt load by preventing a fall in glomerular filtration rate (GFR). We further propose that deletion of the cilia or NOS1 of the macula densa prevents flow modulation of TGF responsiveness and impairs the excretion of a salt load by preventing the rise in GFR following volume expansion, hence promotes the development of salt-sensitive hypertension.

Public Health Relevance

In this proposal we will study the role and mechanisms of tubuloglomerular feedback modulated by the primary cilia and nitric oxide in control of renal hemodynamics, salt and water balance and blood pressure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
7R01DK099276-02
Application #
8895614
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ketchum, Christian J
Project Start
2014-06-01
Project End
2018-05-31
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$195,200
Indirect Cost
$64,631
Name
University of South Florida
Department
Physiology
Type
Schools of Medicine
DUNS #
069687242
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Wang, Ximing; Chandrashekar, Kiran; Wang, Lei et al. (2016) Inhibition of Nitric Oxide Synthase 1 Induces Salt-Sensitive Hypertension in Nitric Oxide Synthase 1α Knockout and Wild-Type Mice. Hypertension 67:792-9
Lu, Yan; Wei, Jin; Stec, David E et al. (2016) Macula Densa Nitric Oxide Synthase 1β Protects against Salt-Sensitive Hypertension. J Am Soc Nephrol 27:2346-56
Song, J; Lu, Y; Lai, E Y et al. (2015) Oxidative status in the macula densa modulates tubuloglomerular feedback responsiveness in angiotensin II-induced hypertension. Acta Physiol (Oxf) 213:249-58
Wang, Xuexiang; Johnson, Ashley C; Williams, Jan M et al. (2015) Nephron Deficiency and Predisposition to Renal Injury in a Novel One-Kidney Genetic Model. J Am Soc Nephrol 26:1634-46
Wang, Lei; Shen, Chunyu; Liu, Haifeng et al. (2015) Shear stress blunts tubuloglomerular feedback partially mediated by primary cilia and nitric oxide at the macula densa. Am J Physiol Regul Integr Comp Physiol 309:R757-66
Wang, Hong; D'Ambrosio, Martin A; Ren, YiLin et al. (2015) Tubuloglomerular and connecting tubuloglomerular feedback during inhibition of various Na transporters in the nephron. Am J Physiol Renal Physiol 308:F1026-31
Lu, Yan; Zhang, Rui; Ge, Ying et al. (2015) Identification and function of adenosine A3 receptor in afferent arterioles. Am J Physiol Renal Physiol 308:F1020-5
Liu, Zhi Zhao; Schmerbach, Kristin; Lu, Yuan et al. (2014) Iodinated contrast media cause direct tubular cell damage, leading to oxidative stress, low nitric oxide, and impairment of tubuloglomerular feedback. Am J Physiol Renal Physiol 306:F864-72
Zhang, Jie; Chandrashekar, Kiran; Lu, Yan et al. (2014) Enhanced expression and activity of Nox2 and Nox4 in the macula densa in ANG II-induced hypertensive mice. Am J Physiol Renal Physiol 306:F344-50

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